Table 1.
Indirect Inhibitors of RAS
| Name | Potency | Type | Binding Site | Mechanism of Action | Model Tested | Clinical Trials | Selected References |
|---|---|---|---|---|---|---|---|
| Peptidomimetic FTase Inhibitors (FTI) | IC50 = 0.5–830nM | FTI | Catalytic domain of FTase | ↓ RAS farnesylation and membrane attachment | Cell culture; Mouse models of pancreatic, lung, and breast cancer | (James, et al., 1993; Kohl, et al., 1994; Reiss, et al., 1990) | |
| Natural Products-Based FTIs and Derivatives | IC50 = 12nm-13μM | FTI | Catalytic domain of FTase | ↓ RAS farnesylation and membrane attachment | Cell culture; Mouse fibrosarcoma model | (Gibbs, et al., 1993; Hara, et al., 1993) | |
| Lonafarnib (SCH-66336) | IC50 = 1.9nM | FTase inhibitor | FTase | ↓ RAS farnesylation and membrane attachment | Cell culture; Mouse models; Cancer clinical trials; Progeria clinical trials | Used in nearly 40 clinical trials for various cancers, progeria, and Hep D. Progeria: NCT00425607 Hep D.: NCT03719313 | (Desjardins, et al., 2011; Eskens, et al., 2001; Gordon, et al., 2018; Kieran, et al., 2007; Kim, et al., 2005; Njoroge, et al., 1998; Ravoet, et al., 2008; Yurdaydin, et al., 2018) |
| Tipifarnib (R115777) | IC50 = 7.9nM | FTase inhibitor | FTase | ↓ RAS farnesylation and membrane attachment | Cell culture; Mouse models; Clinical trials; Currently in Phase II clinical trials for head and neck tumors. | Used in over 80 trials for various cancers; Currently: NCT02383927, NCT03496766 | (Alsina, et al., 2004; Burnett, et al., 2012; Crul, et al., 2002; End, et al., 2001; Rao, et al., 2004) |
| BMS-214662 | IC50 = 100nM (HRAS); >2.5μM (KRAS) | FTase inhibitor | Catalytic domain of FTase | ↓ RAS farnesylation and membrane attachment | Cell culture; Mouse models of lung, colon, bladder, gastric, and pancreatic cancer; Phase I clinical trials – mostly solid tumors | NCT00006242 NCT00006213 NCT00005973 NCT00022529 NCT00006018 NCT00004877 | (Rose, et al., 2001) |
| L-744832 | IC50 = 2–20μM | FTase inhibitor | FTase | ↓ RAS farnesylation and membrane attachment | Cell culture; | (Sepp-Lorenzino, et al., 1995) | |
| DPI-1 and DPI-2 | IC50 = 340nM (DPI-1); 207nM (DPI-2) | Dual prenylation inhibitor (DPI) | FTase and GGTase | ↓ RAS family prenylation and membrane attachment | Cell culture; Mouse model of pancreatic cancer | (Lobell, et al., 2001) | |
| GGTI-2418 | GGTase inhibitor | GGTase | ↓ RALA, RALB, CDC42, and RAC geranylgeranylation and membrane attachment | Phase I trial for advanced solid tumors | NCT03900442 | (Karasic, et al., 2019) | |
| L-778,123 | IC50 = 100nm-162μM | DPI | FTase and GGTase | ↓ RAS family prenylation and membrane attachment | Cell culture; Phase I trial for solid and liquid tumors | NCT00003430 NCT00004057 | (Hahn, et al., 2002; Lobell, et al., 2002; Morgan, et al., 2012) |
| Bisphospohates/ Zoledronic acid | FPPS inhibitor | FPPS | ↓ farnesyl and geranylgeranyl lipid synthesis, RAS lipidation, and membrane localization | Cell culture; Mouse models and human trials of pancreatic, prostate, lung, and breast cancer; Clinical trials | Used in 100s of clinical trials, primarily for bone-related maladies | (Salzano, et al., 2016; Xu, et al., 2019) | |
| NSC1011 and derivatives | IC50 ≈ 5 – 10μM | RCE1 inhibitor | RCE1 | ↓ RAS membrane localization | Cell culture | (Mohammed, et al., 2016) | |
| Cysmethynil and derivatives | IC50 ≈ 2 – 25μM | ICMT inhibitor | ICMT | ↓ RAS membrane localization | Cell culture | (Ramanujulu, et al., 2013) | |
| Salirasib | Kd = 2 –10μM | Farnesylcysteine mimetic | Galectins | ↓ Activated RAS membrane localization | Cell culture; Mouse models of neurofibromatosis, colon cancer, and pancreatic cancer; Phase I and II trials for solid tumors | NCT00531401 | (Borthakur, et al., 2007; Bustinza-Linares, et al., 2010; Furuse, et al., 2018; Riely, et al., 2011; Rotblat, et al., 2008) |
| Palmostatin B | IC50 = 670nM | APT inhibitor | APT | ↑Random H/NRAS membrane distribution | Cell culture | (Dekker, et al., 2010) | |
| Deltarasin | Kd = 41nM | PDEδ inhibitor | Prenyl-binding pocket | ↓ KRAS/PDEδ interaction and RAS trafficking to the plasma membrane | Cell culture; Mouse pancreatic cancer model | (Zimmermann, et al., 2013) | |
| Deltazinone 1 | Kd = 8nM | PDEδ inhibitor | Prenyl-binding pocket | ↓ KRAS/PDEδ interaction and RAS trafficking to the plasma membrane | Cell culture | (Papke, et al., 2016) | |
| Deltasonamide 1 and 2 | Kd = 203pM (1) Kd = 385pM (2) |
PDEδ inhibitor | Prenyl-binding pocket | ↓ KRAS/PDEδ interaction and RAS trafficking to the plasma membrane | Cell culture | (Martin-Gago, et al., 2017) | |
| Deltaflexin-1 and -2 | IC50 ≅ 10μM | PDEδ inhibitor | Prenyl-binding pocket | ↓ KRAS/PDEδ interaction and RAS trafficking to the plasma membrane | Cell culture | (Siddiqui, et al., 2020) | |
| NSC87877 | IC50 ≅ 300nM | SHP1/2 inhibitior | Catalytic domain | ↑pY32 / ↓effector binding | Cell culture; Mouse leukemia model | (Chen, et al., 2006; Perez-Fernandez, et al., 2019; Tsutsumi, et al., 2018) | |
| II-B08 | IC50 = 5.5μM | SHP2 inhibitor | Catalytic domain | ↑pY32 / ↓effector binding | Cell culture; Mouse glioma model | (Bunda, et al., 2015; Tsutsumi, et al., 2018; Zhang, et al., 2010) | |
| 11a-1 | IC50 = 200nM | SHP2 inhibitor | Catalytic domain | ↑pY32 / ↓effector binding | 2/3D cell culture | (Kano, et al., 2019; Tsutsumi, et al., 2018; Zeng, et al., 2014a) | |
| PHPS1 | IC50 = 2.1μM; Ki = 0.73μM | SHP2 inhibitor | Catalytic domain | ↑pY32 / ↓effector binding | Ex vivo 3D-transdifferentiation assay | (Hellmuth, et al., 2008; Ruess, et al., 2018; Zhao et al., 2019) | |
| GS493 | IC50 = 71nM | SHP2 inhibitor | Catalytic domain | ↑pY32 / ↓effector binding | Cell culture; Mouse pancreatic and lung cancer models | (Grosskopf, et al., 2015; Ruess, et al., 2018; Tsutsumi, et al., 2018) | |
| cmpd #57 | SHP2 inhibitor | SHP2 | ↑pY32 / ↓effector binding | Cell culture | (Mainardi, et al., 2018) | ||
| SHP099 | IC50 = 71nM | SHP2 inhibitor | N-terminal/C-terminal/Phosphatase domain interface | ↑pY32 / ↓effector binding | Cell culture; Mouse pancreatic, lung, ovarian, and breast cancer models | (Chen, et al., 2016; Jiang, et al., 2019; Kano, et al., 2019; Pandey, et al., 2019; Wong, et al., 2018; Zhao, et al., 2019) | |
| TNO155 | SHP2 inhibitor | SHP2 | ↑pY32 / ↓effector binding | Phase I clinical trial dose finding study for patients with advanced solid tumors | NCT03114319 | ||
| JAB-3068 | SHP2 inhibitor | SHP2 | ↑pY32 / ↓effector binding | Phase I clinical trial dose finding study for patients with advanced solid tumors | NCT03565003 | ||
| RMC-4550 | EC50 = 49nM | SHP2 inhibitor | SHP2 allosteric site | ↓ Nucleotide exchange | Cell culture; Mouse xenografts | (Nichols, et al., 2018) | |
| RMC-4630 | SHP2 inhibitor | SHP2 | ↑pY32 / ↓effector binding | Phase I clinical trial dose finding study for patients with advanced relapsed or refractory solid tumors | NCT03634982 | ||
| Bryostatin-1 | PKC agonist/inhibitor | PKC | ↑pS181 on RAS/inhibition of RAS phosphorylation | Cell culture; Mouse xenografts; 30+ Phase I and II trials for solid and liquid tumors | NCT00031694 NCT00006389 | (Barcelo, et al., 2014; Bivona, et al., 2006; Lam, et al., 2010; Mohammad, et al., 1998) | |
| Prostratin | PKC agonist | PKC | Cell culture; Mouse transformed fibroblast and pancreatic cancer models | (Wang, et al., 2015) | |||
| Edelfosine | PKC inhibitor | PKC | Inhibition of RAS phosphorylation | Mouse xenografts | (Barcelo, et al., 2014) |